Cisplatin kills ovarium cancer cells through the TRPV1-mediated mitochondrial oxidative stress and apoptosis: TRPV1 inhibitor role of eicopentotaneoic acid

Abstract

The most commonly used treatment, cisplatin (Cisp), causes excessive Ca2+ influx mediated by TRPV1 and produces a high concentration of mitochondrial free reactive oxygen radicals (mROS). In clinical trials, it can be used with other adjuvant medicinal agents to increase safety and efficacy. Although there are contradictory findings, eicosapentaenoic acid (EPA) as an adjuvant has been demonstrated to suppress the proliferation of ovarian cancer cells. We assessed the effects of EPA and Cisp incubations on oxidant, lysosomal injury, and apoptotic values in the OVCAR-3 ovarian tumor cell line by activating TRPV1. Five groups were induced with Cisp (25 µM for 24h), EPA (100 µM for 24h), Cisp + EPA, and Cisp + TRPV1 antagonist (capsazepine, CPZ). We discovered that, in comparison to control cells, Cisp-mediated upregulation of TRPV1 protein is downregulated by EPA and CPZ, but Cisp mediates greater TRPV1-induced Ca2+ entry in cells. The major mROS in cells that cause Cisp-mediated TRPV1 activation include increases in mROS but decreases in glutathione, glutathione peroxidase, mitochondrial function, OVCAR-3 viability, and number. In response to capsaicin, Cisp-mediated TRPV1 stimulation causes mitochondrial Ca2+ and Zn2+ overload, which is followed by increases of caspase-3/-8/-9, lysosomal injury, and apoptosis, however, these effects were less pronounced in the Cisp + EPA and Cisp + CPZ groups. To sum up, we first showed that Cisp kills OVCAR-3 cells by stimulating TRPV1, even while blocking the channel reduced the anti-cancer effects of Cisp. Cisp and TRPV1 stimulators together may provide an alternative method of killing ovarian tumor cells.